Volume 70, Number 3, 2019

Pages 621-628

Nickolas Terry, Alberto Masliah, Cassia Overk, Eliezer Masliah
Remembering Robert D. Terry at a Time of Change in the World of Alzheimer’s Disease

Pages 629-654

Christian LoBue, Catherine Munro, Jeffrey Schaffert, Nyaz Didehbani, John Hart, Jr., Hunt Batjer, C. Munro Cullum
Traumatic Brain Injury and Risk of Long-Term Brain Changes, Accumulation of Pathological Markers, and Developing Dementia: A Review
Abstract: Traumatic brain injuries (TBI) have received widespread media attention in recent years as being a risk factor for the development of dementia and chronic traumatic encephalopathy (CTE). This has sparked fears about the potential long-term effects of TBI of any severity on cognitive aging, leading to a public health concern. This article reviews the evidence surrounding TBI as a risk factor for the later development of changes in brain structure and function, and an increased risk of neurodegenerative disorders. A number of studies have shown evidence of long-term brain changes and accumulation of pathological biomarkers (e.g., amyloid and tau proteins) related to a history of moderate-to-severe TBI, and research has also demonstrated that individuals with moderate-to-severe injuries have an increased risk of dementia. While milder injuries have been found to be associated with an increased risk for dementia in some recent studies, reports on long-term brain changes have been mixed and often are complicated by factors related to injury exposure (i.e., number of injuries) and severity/complications, psychiatric conditions, and opioid use disorder. CTE, although often described as a neurodegenerative disorder, remains a neuropathological condition that is poorly understood. Future research is needed to clarify the significance of CTE pathology and determine whether that can explain any clinical symptoms. Overall, it is clear that most individuals who sustain a TBI (particularly milder injuries) do not experience worse outcomes with aging, as the incidence for dementia is found to be less than 7% across the literature.

Pages 655-658
Short Communication

Sara López-García, Julio Jiménez-Bonilla2, Anjana López Delgado3, Pedro Orizaola Balaguer3, Jon Infante Ceberio1, Ignacio Banzo Marraco, Eloy Rodríguez Rodríguez, Pascual Sánchez-Juan
A Rare PSEN1 (Leu85Pro) Mutation Causing Alzheimer's Disease in a 29-Year-Old Woman Presenting as Corticobasal Syndrome
Abstract: Dementia is not just a disease of old age. Early-onset dementia affects people younger than 65 and its differential diagnosis is broader than in older people. Nevertheless, although young people are considerably more liable to develop a rare form of dementia, Alzheimer’s disease (AD) remains the most common diagnosis. The aim of this article is to report on an early-onset AD patient associated with the rare pathogenic variant PSEN1 (Leu85Pro) presenting as a possible corticobasal syndrome with asymmetric limb apraxia, parkinsonian signs, and myoclonus.

Pages 659-666
Short Communication

Nobutaka Sakae, Michael G. Heckman, Emily R. Vargas, Minerva M. Carrasquillo, Melissa E. Murray, Koji Kasanuki, Nilufer Ertekin-Taner, Steven G. Younkin, Dennis W. Dickson
Evaluation of Associations of Alzheimer’s Disease Risk Variants that Are Highly Expressed in Microglia with Neuropathological Outcome Measures
Abstract: A number of Alzheimer’s disease (AD) susceptibility loci are expressed abundantly in microglia. We examined associations between AD risk variants in genes that are highly expressed in microglia and neuropathological outcomes, including cerebral amyloid angiopathy (CAA) and microglial activation, in 93 AD patients. We observed significant associations of CAA pathology with APOE ε4 and PTK2B rs28834970. Nominally significant associations with measures of microglial activation in white matter were observed for variants in PTK2B, PICALM, and CR1. Our findings suggest that several AD risk variants may also function as disease modifiers through amyloid-β metabolism and white matter microglial activity.

Pages 667-680
Seokjo Kang, Sung Min Son, Sung Hoon Baik, Jinhee Yang, Inhee Mook-Jung (Handling Associate Editor: Bhumsoo Kim)
Autophagy-Mediated Secretory Pathway Is Responsible for Both Normal and Pathological Tau in Neurons
Abstract: Increased levels of total tau (t-tau) and hyperphosphorylated tau (p-tau) proteins in the cerebrospinal fluid of Alzheimer’s disease (AD) patients are well documented and strongly correlate with AD pathology. Recent studies have further shown that human tau can be released into the extracellular space and transferred to nascent neurons. However, because the tau protein has no signal peptide identity, the mechanisms underlying its secretion remain poorly understood. In the present study, we confirmed that tau protein secretion was promoted by autophagy inducers and downregulated by beclin1 knockdown or autophagy inhibitors derived from human wild type tau (wt-tau)-overexpressing SH-SY5Y cells. Moreover, both t-tau and p-tau secretion were increased by autophagy activation. Furthermore, we identified that six isoforms of tau protein are secreted in an autophagy-dependent manner. These results indicate that both normal and pathological tau are secreted via an autophagy-mediated secretory pathway in neurons. Understanding this new pathway for tau secretion may provide critical future insights into tau pathologies, such as AD.

Pages 681-690
Marelle Heesterbeek, Eddy Anton van der Zee, Marieke Joan Gerda van Heuvelen
Feasibility of Three Novel Forms of Passive Exercise in a Multisensory Environment in Vulnerable Institutionalized Older Adults with Dementia
Abstract: Background: Increasing physical activity levels in patients with dementia can reduce pathology severity and progression of the disease. However, physical activity programs can be challenging to adhere to for this vulnerable population. Three novel forms of passive exercise in a multisensory environment may be feasible alternatives for patients who can no longer be involved in physical activity. Objective: To determine the feasibility of three different forms of passive exercise in a multisensory environment in inactive institutionalized older adults with dementia. Methods: 120 patients with dementia participated in this single blind randomized controlled trial (64.5% female, age 85.3±6.8 years Mini-Mental State Examination range 0-29). Ninety participants were randomly assigned to one of the three intervention groups: Therapeutic Motion Simulation (TMSim), Whole Body Vibration (WBV), and TMSim+WBV. Participants received 6 weeks of passive exercise, 4 sessions a week, 4 (WBV) to 12 (TMSim and TMSim+WBV) minutes per session. Feasibility of the novel forms of passive exercise was evaluated based on attendance, compliance, (proxy) experience scores, adverse events and drop-out rates. Results: On average 87.9% of the offered intervention sessions were attended. All three forms of passive exercise were well appreciated by the participants (7.3 on a scale from 0 to 10). Intervention related drop-out rates were reasonable (12.2%) and no serious adverse events occurred. Conclusion: The novel passive exercise interventions TMSim, WBV, and TMSim+WBV are feasible to apply in patients at all stages of dementia. More research is needed to establish effectiveness of passive exercise to limit adverse effects of dementia.

Pages 691-713
Ignazio S. Piras, Jonida Krate, Elaine Delvaux, Jennifer Nolz, Diego F. Mastroeni, Antonio M. Persico, Wayne M. Jepsen, Thomas G. Beach, Matthew J. Huentelman, Paul D. Coleman (Handling Associate Editor: Colin Combs)
Transcriptome Changes in the Alzheimer’s Disease Middle Temporal Gyrus: Importance of RNA Metabolism and Mitochondria-Associated Membrane Genes
Abstract: We used Illumina Human HT-12 v4 arrays to compare RNA expression of middle temporal gyrus (MTG; BA21) in Alzheimer’s disease (AD = 97) and non-demented controls (ND = 98). A total of 938 transcripts were highly differentially expressed (adj p < 0.01; log2 FC ≥ |0.500|, with 411 overexpressed and 527 underexpressed in AD. Our results correlated with expression profiling in neurons from AD and ND obtained by laser capture microscopy in MTG from an independent dataset (log2 FC correlation: r = 0.504; p = 2.2e-16). Additionally, selected effects were validated by qPCR. ANOVA analysis yielded no difference between genders in response to AD, but some gender specific genes were detected (e.g., IL8 and AGRN in males, and HSPH1 and GRM1 in females). Several transcripts were associated with Braak staging (e.g., AEBP1 and DNALI1), antemortem MMSE (e.g., AEBP1 and GFAP), and tangle density (e.g., RNU1G2, and DNALI1). At the pathway level, we detected enrichment of synaptic vesicle processes and GABAergic transmission genes. Finally, applying the Weighted Correlation Network Analysis, we identified four expression modules enriched for neuronal and synaptic genes, mitochondria-associated membrane, chemical stimulus and olfactory receptor and non-coding RNA metabolism genes. Our results represent an extensive description of MTG mRNA profiling in a large sample of AD and ND. These data provide a list of genes associated with AD, and correlated to neurofibrillary tangles density. In addition, these data emphasize the importance of mitochondrial membranes and transcripts related to olfactory receptors in AD.

Pages 715-722
Raymond R. Romano III, Alison R. Anderson, Michelle D. Failla, Mary S. Dietrich, Sebastian Atalla, Michael A. Carter, Todd B. Monroe
Sex Differences in Associations of Cognitive Function with Perceptions of Pain in Older Adults
Abstract: Background: Sex differences in pain have been shown to exist in older adults with normal cognition and people with Alzheimer’s disease. It is unknown if sex differences in pain in older adults exist in a range of communicative older adults with varying cognitive ability from no impairment to moderately severe cognitive impairment. Objective: This study proposes to compare the association between psychophysical responses to experimental thermal pain between males and females to determine if sex differences in pain exist across the cognitive spectrum. Methods: We conducted a secondary analysis of data from an age- and sex-matched between-groups cross-sectional study examining the psychophysical response to contact heat in people with and without dementia. Results: Median age of males (n=38) and females (n=38) was 73 (range: 68-87) with similar distributions of Mini-Mental State Examination (MMSE) scores (range: 11-30). Findings revealed inverse statistically significant associations with the threshold temperature of warmth (females: r=-0.41, p=0.010; males: r=-0.33, p=0.044). There was an apparent divergent pattern of MMSE associations with unpleasantness ratings between the groups. At the moderate pain threshold, that difference became statistically significant (p=0.033). Females demonstrated a positive association of MMSE with unpleasantness (r=0.30, p=0.072), while males demonstrated an inverse association at that respective threshold (r =-0.20, p=0.221). Conclusions: Between-group findings suggest that patterns of responses to thermal stimulus intensity may differ between males and females with worsening cognition with females reporting significantly less unpleasantness with the percept of moderate pain and males reporting significantly higher unpleasantness with moderate pain perception.

Pages 723-732
Carolina Alves, Lília Jorge, Nádia Canário, Beatriz Santiago, Isabel Santana, João Castelhano, António Francisco Ambrósio, Rui Bernardes, Miguel Castelo-Branco
Interplay between Macular Retinal Changes and White Matter Integrity in Early Alzheimer’s Disease
Abstract: This study aims to investigate the relationship between structural changes in the retina and white matter in the brain, in early Alzheimer’s disease (AD). Twenty-three healthy controls (mean age = 63.4 ± 7.5 years) and seventeen AD patients (mean age = 66.5 ± 6.6 years) were recruited for this study. By combining two imaging techniques—optical coherence tomography and diffusion tensor imaging (DTI)—the association between changes in the thickness of individual retinal layers and white matter dysfunction in early AD was assessed. Retinal layers were segmented, and thickness measurements were obtained for each layer. DTI images were analyzed with a quantitative data-driven approach to evaluating whole-brain diffusion metrics, using tract-based spatial statistics. Diffusion metrics, such as fractional anisotropy, are markers for white matter integrity. Multivariate and partial correlation analyses evaluating the association between individual retinal layers thickness and diffusion metrics were performed. We found that axial diffusivity, indexing axonal integrity, was significantly reduced in AD (p = 0.016, Cohen’s d = 1.004) while in the retina, only a marginal trend for significance was found for the outer plexiform layer (p = 0.084, Cohen’s d = 0.688). Furthermore, a positive association was found in the AD group between fractional anisotropy and the inner nuclear layer thickness (p < 0.05, r = 0.419, corrected for multiple comparisons by controlling family-wise error rate). Our findings suggest that axonal damage in the brain dominates early on in this condition and shows an association with retinal structural integrity already at initial stages of AD. These findings are consistent with an early axonal degeneration mechanism in AD.

Pages 733-745
Jenni Ilomäki, Laura Fanning, Claire Keen, Janet K. Sluggett, Amy T. Page, Maarit J. Korhonen , Atte Meretoja, Kevin P. Mc Namara, J. Simon Bell
Trends and Predictors of Oral Anticoagulant Use in People with Alzheimer’s Disease and the General Population in Australia
Abstract: Background: People with Alzheimer’s disease (AD) are less likely to use oral anticoagulants than people without AD. Objective: We investigated incidence and prevalence of warfarin and direct oral anticoagulant (DOAC) use, and determined predictors of DOAC and warfarin initiation in older people with AD and the general population. Methods: Australian Pharmaceutical Benefits Scheme data for 356,000 people aged ≥65 years dispensed warfarin or DOACs during July 2013-June 2017 were analyzed. Changes in annual incidence and prevalence were estimated using Poisson regression. Predictors of DOAC versus warfarin initiation were estimated using multivariable logistic regression separately for people with AD and the general population. Results: Oral anticoagulant prevalence increased from 8% in people with AD and 9% in the general population to 12% in both groups from 2013/2014 to 2016/2017. DOAC prevalence increased (from 2.4% to 7.8% in people with AD, 3.2% to 7.7% in the general population) while warfarin prevalence declined (6.6% to 4.5%, 7.0% to 4.3%, correspondingly). The incidence of warfarin use decreased by 45-55%. In people with AD, women were less likely to initiate DOACs than men, whereas presence of arrhythmias or pain/inflammation increased likelihood of initiating DOACs. Age ≥85 years, cardiovascular diseases, gastric acid disorder, diabetes, and end-stage renal disease were associated with lower odds of DOAC initiation in the general population. Conclusion: DOAC introduction has coincided with increased anticoagulation rates in people with AD. Rates are now similar in older people with AD and the general population. Compared to previous years, DOACs are now more likely to be initiated, particularly for those aged ≥85 years.

Pages 747-756
Yue Cui, Sisi Dai, Zupei Miao, Yu Zhong, Yang Liu, Lin Liu, Donglai Jing, Yanyan Bai, Yu Kong, Wei Sun, Fang Li, Guo Qihao, Pedro Rosa-Neto, Serge Gauthier, Liyong Wu
Reliability and Validity of the Chinese Version of the Mild Behavioral Impairment Checklist for Screening for Alzheimer’s Disease
Abstract: Background: The Mild Behavioral Impairment Checklist (MBI-C), a screening scale for neuropsychiatric symptom evaluation, facilitates Alzheimer's disease (AD) screening. However, its validity and reliability for use as an AD screening tool have not been determined. Objective: To develop an AD screening scale suitable for the Chinese population. Methods: The MBI-C was translated into Chinese and back-translated with the original author’s consent. Forty-six AD patients, attending the Xuanwu hospital memory clinic, and 50 sex- and education-matched controls from the community underwent a full neuropsychological evaluation, including MBI-C assessment. Among them, 15 AD patients were evaluated repeatedly, and eight were evaluated simultaneously by two different clinicians, to assess MBI-C reliability. Results: The MBI-C demonstrated good internal consistency reliability, test–retest reliability, and inter-rater reliability. Its optimal cutoff point was 6/7 for identifying AD dementia, with a sensitivity of 86.96% and specificity of 86.00%, and its detection rate for moderate–severe AD dementia was higher than that of the Neuropsychiatric Inventory Questionnaire (NPI-Q). Pearson’s correlation coefficients ranged from 0.702 to 0.831, indicating content validity. Seven factors were extracted during principal component analysis, with a cumulative contribution of 70.55%. Moreover, the Pearson’s correlation coefficient was 0.758, indicating its criterion validity. The MBI-C could also distinguish AD dementia severity. MBI-C scores were significantly negatively correlated with MMSE and MoCA scores, and positively correlated with ADL scores. Conclusion: This study showed that the Chinese version of MBI-C has high reliability and validity, and could replace the NPI-Q for AD dementia screening in the Chinese population.

Pages 757-792
Ioulietta Lazarou, Thanos G. Stavropoulos, Georgios Meditskos, Stelios Andreadis, Ioannis (Yiannis) Kompatsiaris, Magda Tsolaki
Long-Term Impact of Intelligent Monitoring Technology on People with Cognitive Impairment: An Observational Study
Abstract: Background: Interactive smart home systems are particularly useful for people with cognitive impairment. Objective: To investigate the long-term effects of Assistive Technology (AT) combined with tailored non-pharmacological interventions for people with cognitive impairment. Methods: 18 participants (12 with mild cognitive impairment and 6 with Alzheimer’s disease) took part in the study that we evenly allocated in one of three groups: 1) experimental group (EG), 2) control group 1 (CG1), and 3) CG2. EG received the system installed at home for 4 to 12 months, during which they received tailored non-pharmacological interventions according to system observations. CG1 received tailored interventions for the same period, but only according to state-of-the-art self-reporting methods. Finally, CG2 neither had a system installation nor received interventions. All groups underwent neuropsychological assessment before and after the observational period. Results: After several months of continuously monitoring at home and deployment of tailored interventions, the EG showed statistically significant improvement in cognitive function, compared to the CG1 and CG2. Moreover, EG participants, who received the sensor-based system, have shown improvement in domains such as sleep quality and daily activity, as measured by the multi-sensor system. In addition, the feedback collected from the participants concludes that the long-term use of the multi-sensor system by people with cognitive impairment can be both feasible and beneficial. Conclusion: Deploying a sensor-based system at real home settings of people with cognitive limitations living alone and maintaining its use long-term is not only possible, but also beneficial for clinical decision making in order to tackle cognitive, functional, and behavioral related problems.

Pages 793-810
Manuela Bomba*, Alberto Granzotto*, Vanessa Castelli, Marco Onofrj, Rossano Lattanzio, Annamaria Cimini, Stefano L. Sensi *These authors contributed equally to this work.
Exenatide Reverts the High-Fat-Diet-Induced Impairment of BDNF Signaling and Inflammatory Response in an Animal Model of Alzheimer’s Disease
Abstract: Alzheimer’s disease (AD) is a multifactorial condition in which, along with amyloid-β (Aβ) and tau-related pathology, the synergistic activity of co-morbidity factors promote the onset and progression of the disease. Epidemiological evidence indicates that glucose intolerance, deficits in insulin secretion, or type-2 diabetes mellitus (T2DM) participate in increasing cognitive impairment or dementia risk. Insulin plays a pivotal role in the process as the hormone critically regulates brain functioning. GLP-1, the glucagon-like peptide 1, facilitates insulin signaling, regulates glucose homeostasis, and modulates synaptic plasticity. Exenatide is a synthetic GLP-1 analog employed in T2DM. However, exenatide has also been shown to affect the signaling of the brain-derived neurotrophic factor (BDNF), synaptic plasticity, and cognitive performances in animal models. In this study, we tested whether exenatide exerts neuroprotection in a preclinical AD model set to mimic the clinical complexity of the human disease. We investigated the effects of exenatide treatment in 3xTg-AD mice challenged with a high-fat diet (HFD). Endpoints of the study were variations in systemic metabolism, insulin and neurotrophic signaling, neuroinflammation, Aβ and tau pathology, and cognitive performances. Results of the study indicate that exenatide reverts the adverse changes of BDNF signaling and the neuroinflammation status of 3xTg-AD mice undergoing HFD without affecting systemic metabolism or promoting changes in cognitive performances.

Pages 811-824
Geoffroy Gagliardi, Stéphane Epelbaum, Marion Houot, Hovagim Bakardjian, Laurie Boukadid, Marie Revillon, Bruno Dubois, Gianfranco Dalla Barb*, Valentina La Corte*, for the INSIGHT-preAD study group *These authors contributed equally to this work.
Which Episodic Memory Performance Is Associated with Alzheimer’s Disease Biomarkers in Elderly Cognitive Complainers? Evidence from a Longitudinal Observational Study with Four Episodic Memory Tests (Insight-PreAD)
Abstract: Background: Alzheimer’s disease (AD) pathology is found in the brain years before symptoms are usually detected. An episodic memory (EM) decline is considered to be the specific cognitive sign indicating a transition from the preclinical to the prodromal stage of AD. However, there is still no consensus on the most sensitive tool to detect it. Objective: The goal of our study was to determine which EM measures, among three clinically used EM tests and one research EM test, would be optimal to use for detection of early decline in elderly cognitive complainers. Methods: 318 healthy elderly participants with subjective cognitive complaint were followed for two years. We applied generalized linear mixed models to investigate the effect of baseline brain amyloid and metabolism on the longitudinal evolution of four EM tests. Results: Our findings show that participants performed significantly worse in two out of four EM tests (i.e., the Memory Binding Test and the Delayed Matched Sample test 48 items) as their level of brain amyloid load increased. However, we did not find an association between EM measures and brain metabolism. An interaction of the two biomarkers was associated with the number of intrusions in the Memory Binding Test over two years. Conclusion: As most clinical trials in AD are now including patients at its early clinical stage, the precise delineation of the transition phase between the preclinical and prodromal stages of the disease is of crucial importance. Our study indicates that challenging EM tests and intrusions are valuable tools to identify this critical transition.

Pages 825-842
Rebecca Erwin Wells, Catherine Kerr, Michelle L. Dossett, Suzanne C. Danhauer, Stephanie J. Sohl, Bonnie C. Sachs, Jacquelyn Walsh Feeley, Jennifer Wolkin, Robert Wall, Ted Kaptchuk, Daniel Press, Russell S. Phillips, Gloria Y. Yeh (Handling Associate Editor: Dharma Singh Khalsa)
Can Adults with Mild Cognitive Impairment Build Cognitive Reserve and Learn Mindfulness Meditation? Qualitative Theme Analyses from a Small Pilot Study
Abstract: Background/Objective: High levels of chronic stress negatively impact the hippocampus and are associated with increased incidence of mild cognitive impairment (MCI) and Alzheimer’s disease. While mindfulness meditation may mitigate the effects of chronic stress, it is uncertain if adults with MCI have the capacity to learn mindfulness meditation. Methods: 14 adults with MCI were randomized 2:1 to Mindfulness Based Stress Reduction (MBSR) or a wait-list control group. We conducted qualitative interviews with those who completed MBSR. Transcribed interviews were: a) coded using an emergent themes inductive approach informed by grounded theory; b) rated 0-10, with higher scores reflecting greater perceived benefit from and understanding of mindfulness meditation. Ratings were correlated with daily home practice times and baseline level of cognitive function. Results: Seven themes emerged from the interviews: positive perceptions of class; development of mindfulness skills, including meta-cognition; importance of the group experience; enhanced well-being; shift in MCI perspective; decreased stress reactivity and increased relaxation; improvement in interpersonal skills. Ratings of perceived benefit and understanding ranged from 2-10 (mean=7) and of 0-9.5 (mean=6), respectively. Many participants experienced substantial benefit/understanding, some had moderate, and a few had minimal benefit/understanding. Understanding the key concepts of mindfulness was highly positively correlated with ≥ 20 minutes/day of home practice (r=0.90) but not with baseline cognitive function (r=0.13). Conclusions: Most adults with MCI were able to learn mindfulness meditation and had improved MCI acceptance, self-efficacy, and social engagement. Cognitive reserve may be enhanced through a mindfulness meditation program even in patients with MCI.

Pages 843-860
Yao Zhu, Liang Gong, Cancan He, Qing Wang, Qingguo Ren, Chunming Xie, on behalf of Alzheimer’s Disease Neuroimaging Initiative
Default Mode Network Connectivity Moderates the Relationship between the APOE Genotype and Cognition and Individualizes Identification across the Alzheimer’s Disease Spectrum
Abstract: Although previous studies have investigated the effects of the apolipoprotein E (APOE) ε4 genotype on the default mode network (DMN) in the Alzheimer’s disease (AD) spectrum, it is still unclear how the APOE genotype regulates the DMN and subsequently affects cognitive decline in the AD spectrum. One hundred sixty-nine subjects with resting-state functional magnetic resonance imaging data and neuropsychological test scores were selected from the Alzheimer’s Disease Neuroimaging Initiative. The main effects and interaction of the APOE genotype and disease status on the DMN were explored. A moderation analysis was performed to investigate the relationship among the APOE genotype, DMN connectivity, and cognition. Additionally, the pair-wised DMN connectivity was used to classify AD spectrum, and the classification accuracy was validated. Compared to APOE ε4 non-carriers, APOE ε4 carriers showed the opposite trajectory of DMN connectivity across the AD spectrum. Specifically, the strengths in the posterior cingulate cortex (PCC) connecting with the right precuneus, insular, and fusiform area (FFA) were positively correlated with Mini-Mental State Examination (MMSE) scores in APOE ε4 non-carriers but not in APOE ε4 carriers. Furthermore, PCC-right FFA connectivity could moderate the effects of the APOE genotype on MMSE scores across the disease groups. More importantly, using a receiver operating characteristic analysis, these altered connectivities yielded strong classification powers in a pathological stage-dependent manner in the AD spectrum. These findings first identified the intrinsic DMN connectivity moderating the effect of the APOE genotype on cognition and provided a pathological stage-dependent neuroimaging biomarker for early differentiation of the AD spectrum.

Pages 861-875
Shira Simonovitch, Eran Schmukler, Eliezer Masliah, Ronit Pinkas-Kramarski, Daniel M. Michaelson
The Effects of APOE4 on Mitochondrial Dynamics and Proteins in vivo
Abstract: This study examined the effects of apolipoprotein E4 (APOE4), the most prevalent genetic risk factor for Alzheimer's disease (AD), on proteins involved in mitochondrial dynamics and autophagy, in the hippocampus of targeted replacement mice. Immunohistochemical measurements revealed that the levels of the mitochondrial fusion-mediating protein, MFN1, were higher, whereas those of corresponding fission-regulating protein, DRP-1, were lower in the hippocampus of ApoE4 mice than in the corresponding ApoE3 mice, indicating that APOE4 is associated with increased mitochondrial fusion and decreased fission. A similar ApoE4-driven decrease in DRP-1 was also observed in AD brains. The levels of the mitochondrial proteins COX1 and Tom40, were higher in the ApoE4 mice, which is consistent with the increased fusion. Measurements of the levels of cleaved PINK1 and parkin, which mark and target mitochondria for mitophagic degradation, revealed lower levels of cleaved PINK1, suggesting reduced mitochondrial membrane potential, and higher levels of parkin in the hippocampus of ApoE4 compared with the ApoE3 mice, indicating altered mitophagy. The levels of the ubiquitin-binding scaffold protein, p62/SQSTM1, which directs selected cargo to the autophagosomes, were also higher in the ApoE4 mice. These findings suggest that APOE4 is associated with enhanced mitochondrial fusion and decreased fission. Additionally, the results indicate that the mitophagy/autophagy is reduced in ApoE4 mice, resulting in higher levels of proteins such as parkin and p62, which are normally degraded during this process. Taken together, these results suggest a novel mechanism that may underlie the pathological effects of APOE4 and indicate that use of APOE4 genotyping could pave the way for identification of novel APOE4-related therapeutic targets.

Pages 877-887
Morgan J. Schaeffer, Brandy L. Callahan, for the Alzheimer’s Disease Neuroimaging Initiative
Investigating the Association between Verbal Forgetting and Pathological Markers of Alzheimer’s and Lewy Body Diseases
Abstract: Background: The percentage of verbal forgetting (VF%) measure of the Rey Auditory Verbal Learning Test (RAVLT) has been proposed to differentiate patients diagnosed clinically with Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB). Objective: To determine if VF% aligns with gold-standard biomarker and autopsy evidence of AD and DLB neuropathology. Methods: Clinical, cognitive, sociodemographic, and biomarker data were collected from 315 patients with baseline cognitive impairment and 485 normal controls from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). AD markers included reduced cerebrospinal fluid (CSF) amyloid-β, elevated total-tau and phosphorylated-tau, hippocampal atrophy, and the presence of amyloid plaques and neurofibrillary tangles at autopsy. DLB markers included reduced CSF α-synuclein, preserved hippocampus, atrophied putamen, occipital glucose metabolism, and the presence of Lewy bodies at autopsy. Cognitively impaired participants were classified as ADVF% (n = 190) or DLBVF% (n = 125) based on their RAVLT VF% scores using a 75% cut-off (≥ 75% = ADVF%, < 75% = DLBVF%). Postmortem data were available for 13 ADVF% participants, 13 DLBVF% patients, and six healthy controls. Results: ADVF% and DLBVF% participants did not differ on CSF or neuroimaging biomarkers, with the exception of total tau levels which were higher in ADVF%. In the subset of participants with autopsy data, comorbid AD and DLB pathology was most frequent in ADVF% participants, and pure DLB pathology was most frequent in DLBVF% participants, however, these differences were not statistically significant. Conclusion: The RAVLT VF% measure does not reliably align with AD and DLB neuropathology in ADNI participants.

Pages 889-898
Jeremy Molad, Hen Hallevi, Amos D. Korczyn, Efrat Kliper, Eitan Auriel, Natan M. Bornstein, Einor Ben Assayag
Vascular and Neurodegenerative Markers for the Prediction of Post-Stroke Cognitive Impairment: Results from the TABASCO Study
Abstract: Background: Stroke is a major cause of cognitive impairment and dementia. However, the underlying mechanisms beyond post-stroke cognitive impairment (PSCI) are not fully explained to date. Objective: We studied the contribution of vascular pathology measures to PSCI, separate from and in conjunction with pathologic markers associated with Alzheimer’s disease (AD). Methods: Data from 397 cognitively intact ischemic stroke patients were available. All patients underwent 3T MRI and evaluated for white matter hyperintensity volume (WMHV) and integrity, ischemic lesions, small vessel disease (SVD) markers and grey matter (GM), hippocampal and cerebrospinal fluid (CSF) volumes. Comprehensive cognitive tests were performed on admission and after two years. We used multiple regression to evaluate the contributions of vascular pathology measures (Framingham risk score, WMHV, and existence of SVD) and AD-associated markers (apolipoprotein E4 status and hippocampal volume). Results: During two years follow-up, 80 participants (20.2%) developed PSCI. Low GM and cortex volume and high WMHV and CSF volume, but not the new lesion volume, predicted the development of PSCI in a dose-dependent relationship (p=0.001). Vascular related imaging markers and risk factors predicted PSCI better than AD related markers (p<0.001). Conclusions: Brain structural measures, including total GM volume, WMHV, and CSF volume were independently associated with PSCI and may serve as early biomarkers for risk prediction. In our sample, vascular pathology measures contributed significantly better to PSCI prediction than markers associated with AD. The newly detected ischemic lesion has not emerged as biomarker for PSCI risk, thus maybe a part of the ongoing vascular pathology.

Pages 899-905
Karel Kostev, Pawel Kurylo, Joanna Kosik, Louis Jacob
One-Year Persistence with Donepezil, Memantine, and Rivastigmine in More than 66,000 Elderly Patients Followed in Poland
Abstract: Background: Previous studies have suggested that there are substantial differences between countries in terms of persistence with antidementia drugs and that the management of dementia is likely to be population-specific. Objective: The aim of this study was to analyze the one-year persistence with donepezil, memantine, and rivastigmine in more than 66,000 elderly patients followed in Poland. Methods: This study included patients who were prescribed donepezil, memantine, or rivastigmine for the first time in general and neuropsychiatric practices in Poland between September 2016 and December 2017 (index date; N=66,030). The primary outcome of the study was the one-year persistence with donepezil, memantine, and rivastigmine. Non-persistence was defined as a gap of at least 90 days without anti-dementia therapy. The secondary outcome was the identification of variables significantly associated with treatment non-persistence. Results: After 12 months of follow-up, 42.2% of donepezil users, 46.0% of rivastigmine users, and 65.9% of memantine users were persistent (log-rank p-value<0.001). Memantine (hazard ratio [HR]=0.58) and rivastigmine users (HR=0.92) were less likely to discontinue treatment one year after initiation than donepezil users. Furthermore, a younger age (60-64 years: HR=1.32; 65-74 years: HR=1.13) and therapy initiated by a neuropsychiatrist (HR=1.11) were positively associated with therapy discontinuation, while we observed a negative association between the prescription of anti-psychotic drugs and non-persistence (HR=0.81). Conclusion: One-year persistence with donepezil, memantine, and rivastigmine was low in elderly patients followed in Poland, and was influenced by age, physician specialty, and co-therapy.

Pages 907-915
Alireza Nazarian, Alexander M. Kulminski
Evaluation of the Genetic Variance of Alzheimer’s Disease Explained by the Disease-Associated Chromosomal Regions
Abstract: Heritability analysis of complex traits/diseases is commonly performed to obtain illustrative information about the potential contribution of the genetic factors to their phenotypic variances. In this study, we investigated the narrow-sense heritability (h2) of Alzheimer's disease (AD) using genome-wide single-nucleotide polymorphisms (SNPs) data from three independent studies in the linear mixed models framework. Our meta-analyses demonstrated that the estimated h2 values (and their standard errors) of AD in liability scale were 0.280 (0.091), 0.348 (0.113), and 0.389 (0.126) assuming AD prevalence rates of 10%, 20%, or 30% at ages of 65+, 75+, and 85+ years, respectively. We also found that chromosomal regions containing two or more AD-associated SNPs at p < 5E-08 could collectively explain 37% of the additive genetic variance of AD in our samples. AD-associated regions in which at least one SNP had attained p < 5E-08 explained 56% of the additive genetic variance of AD. These regions harbored 3% and 11% of SNPs in our analyses. Also, the chromosomal regions containing two or more and one or more AD-associated SNPs at p < 5E-06 accounted for 72% and 94% of the additive genetic variance of AD, respectively. These regions harbored 27% and 44% of SNPs in our analyses. Our findings showed that the overall contribution of the additive genetic effects to the AD liability was moderate and age-dependent. Also, they supported the importance of focusing on known AD-associated chromosomal regions to investigate the genetic basis of AD, e.g., through haplotype analysis, analysis of heterogeneity, and functional studies.

Pages 917-924
Janardan P. Pandey, Ronald T. Kothera, Shufeng Liu, Andrea Saul Costa, Roberta Mancuso, Simone Agostini
Immunoglobulin Genes and Immunity to HSV1 in Alzheimer’s Disease
Abstract: Although genome-wide association studies (GWAS) of late-onset Alzheimer’s disease (AD) have identified numerous genes that influence the risk for disease, the majority of the genetic variance of AD remains uncharacterized. Furthermore, current GWAS, despite their name, do not evaluate all genes in the human genome. One such gene complex is immunoglobulin GM (γ marker) genes on chromosome 14. GM genes are excellent candidate genes for AD because they influence immunity to herpes simplex virus type 1 (HSV1), which has been implicated in AD pathology by an increasing number of reports. The aim of this investigation was to determine if particular GM genotypes were associated with AD and mild cognitive impairment (MCI), and whether they contributed to the interindividual differences in the level of anti-HSV1 IgG antibodies. A total of 141 HSV1 seropositive individuals—56 AD patients, 48 MCI individuals, and 37 sex- and age-matched healthy controls—were characterized for GM alleles 3, 17, and 23. The homozygosity for the GM 3 allele was significantly associated with MCI (p=0.025). GM 3/17 heterozygous AD patients had significantly higher levels of anti-HSV1 antibodies than the healthy controls expressing the same genotype (p=0.0004). Among MCI subjects, the GM 3/17 genotype was associated with significantly higher level of anti-HSV1 antibodies as compared to the GM 17/17 homozygous genotype (pc=0.040). Among AD patients, the GM 23+/- genotype was significantly associated with anti-HSV1 antibody responses (pc=0.025). These results suggest that GM genes could act as potential unifiers of the genetic and viral etiology of AD.

Pages 925-936
Qian Yu, Chun-ling Dai, Yongli Zhang, Yanxing Chen, Zhe Wu, Khalid Iqbal, Fei Liu, Cheng-Xin Gong (Handling Associate Editor: Xuemin Xu)
Intranasal Insulin Increases Synaptic Protein Expression and Prevents Anesthesia-Induced Cognitive Deficits Through mTOR-eEF2 Pathway
Abstract: General anesthesia increases the risk for cognitive impairment and Alzheimer’s disease (AD) in vulnerable individuals such as the elderly. We previously reported that prior administration of insulin through intranasal delivery can prevent the anesthesia-induced cognitive impairment and biochemical changes in the brain. However, little is known about the underlying molecular mechanisms. Here, we report that general anesthesia resulted in downregulation of mammalian/mechanistic target of rapamycin (mTOR) and eukaryotic elongation factor 2 (eEF2) in the brain along with reduction of presynaptic proteins and brain-derived neurotrophic factor and cognitive impairment in aged mice. Prior administration of intranasal insulin prevented these anesthesia-induced changes. These results suggest the involvement of the mTOR-eEF2 signaling pathway in the anesthesia-induced brain changes and cognitive impairment and in the prevention of these changes with insulin. Correlation analyses and the use of eEF2 kinase inhibitor further support our conclusions. These studies shed light on the molecular mechanism by which anesthesia and insulin could act on synaptic proteins and cognitive function.

Pages 937-952
Kaori Taniguchi, Fumiko Yamamoto, Takuya Arai, Jinwei Yang, Yusuke Sakai, Masayuki Itoh, Naomi Mamada, Masayuki Sekiguchi, Daisuke Yamada, Akiyoshi Saitoh, Fuyuki Kametani, Akira Tamaoka, Yumiko M. Araki, Keiji Wada, Hidehiro Mizusawa, Wataru Araki
Tyrosol Reduces Amyloid-β Oligomer Neurotoxicity and Alleviates Synaptic, Oxidative, and Cognitive Disturbances in Alzheimer’s Disease Model Mice
Abstract: Soluble amyloid-β (Aβ) oligomers (AβOs), which elicit neurotoxicity and synaptotoxicity, are thought to play an initiating role in the pathology of Alzheimer’s disease (AD). Since AβOs are a key therapeutic target, we attempted to identify natural agents that reduce AβO neurotoxicity. Using an assay system in which primary cultured neurons are treated with AβOs, we found that Rhodiola rosea extracts and one of its main constituents, tyrosol, significantly inhibited AβO-induced caspase-3 activation. We then assessed the in vivo efficacy of tyrosol by oral administration of the compound into AD model (5XFAD) transgenic and non-transgenic mice from either 2 or 4 to 7 months of age. In both paradigms, tyrosol treatment did not affect body weights of mice. Immunohistochemical analysis revealed that the immunoreactivity of spinophilin, a dendritic synaptic protein, was significantly reduced in three hippocampal subregions of vehicle-treated AD mice compared with non-transgenic mice, which was reversed in tyrosol-treated AD mice. Tyrosol treatment also prevented the enhancement of 4-hydroxy-2-nonenal immunoreactivity in the hippocampal CA3 region of AD mice. By contrast, tyrosol administration did not affect Aβ accumulation, as evaluated by immunohistochemical and biochemical analyses. Moreover, the Barnes maze test showed that tyrosol administration modestly mitigated spatial memory impairment in AD mice. These findings collectively indicate that the natural agent tyrosol protects neurons against AβO neurotoxicity in vitro and ameliorates synaptic disturbance, oxidative stress responses, and cognitive impairment in vivo. We thus suggest that tyrosol is potentially an effective, safe, and unique drug candidate for AD.

Pages 953-964
Audrey Low, Kok Pin Ng, Russell Jude Chander, Benjamin Wong, Nagaendran Kandiah
Association of Asymmetrical White Matter Hyperintensities and Apolipoprotein E4 on Cognitive Impairment
Abstract: Background: Asymmetrical patterns of cerebral damage have been widely observed in a range of neurodegenerative diseases, including Alzheimer’s disease (AD). Objective: To elucidate the clinical associations of asymmetrical white matter hyperintensities (WMH) in mild cognitive impairment (MCI) and AD. Methods: Regional WMH asymmetry of 340 participants (90 healthy controls, 132 MCI, 118 AD) was calculated as the difference in normalized hemispheric WMH volume (WMH/ICV) adjusted for structural brain asymmetry of respective lobar regions and total WMH. WMH asymmetry was analyzed in relation to disease classification, cognition, and APOE4 status using ANCOVA and multiple regression analysis, controlling for gender, age, ethnicity, and correcting for multiple comparisons using Bonferroni correction. Moderation analysis examined interaction effects of APOE4 on associations between cognition and WMH asymmetry. Results: Greater left-dominant occipital WMH asymmetry was observed in AD, compared to healthy controls and MCI, and was associated with poorer global cognition, memory, language, and executive functions among cognitively impaired participants (MCI and AD). Cognitively impaired APOE4 carriers displayed greater left-dominant WMH asymmetry in the whole brain and frontal lobe, compared to non-carriers. Importantly, effects were independent of structural brain asymmetry, global cerebral atrophy, and overall WMH burden. Moderation analysis demonstrated associations between left-dominant WMH asymmetry and cognition in cognitively impaired APOE4 non-carriers, but not APOE4 carriers. Conclusion: Leftward asymmetry of WMH may be more pathological in nature, compared to symmetrical WMH. Furthermore, the detrimental effects of WMH asymmetry was more relevant in APOE4-negative cognitive impairment, compared to APOE4-positive which may be driven primarily by AD pathology.